6-(2,4-difluorophenyl)pyrimidine-4-carboxylic acid | 1207723-93-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 6-(2,4-difluorophenyl)pyrimidine-4-carboxylic acid
• CAS: 1207723-93-0
• 化学式: C₁₁H₆F₂N₂O₂
• 分子量: 236.178
• InChiKey: UCSDZWHRNJQLJC-UHFFFAOYSA-N

物化性质

• 沸点：
  416.6±45.0 °C(Predicted)
• 密度：
  1.456±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  63.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-(2,4-difluorophenyl)pyrimidine-4-carboxylic acid 、 1-环己基-4-哌啶胺 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 6-(2,4-difluorophenyl)pyrimidine-4-carboxylic acid (1-cyclohexylpiperidin-4-yl)amide
  参考文献：
  名称：

  发现有效的，选择性的，口服的CXCR7拮抗剂ACT-1004-1239

  摘要：

  趋化因子受体CXCR7，也称为ACKR3，是七种跨膜G蛋白偶联受体（GPCR），涉及多种病理，例如神经系统疾病，自身免疫性疾病和癌症。通过结合和清除趋化因子CXCL11和CXCL12，CXCR7调节它们的细胞外水平。在最初的高通量筛选活动中，出现了热门3。一触即发的优化导致发现了一种新型的化学型系列，例如反式外消旋化合物11i。该系列提供了可阻断CXCL11和CXCL12诱导的β-arrestin募集的CXCR7拮抗剂。11i的三取代哌啶骨架的进一步结构修饰产生具有高CXCR7拮抗活性和平衡ADMET性质的化合物。本文所述的努力最终导致了ACT-1004-1239（28f）的发现。ACT-1004-1239的生物学特性表明它是一种有效的，不可逾越的拮抗剂。在小鼠中口服ACT-1004-1239的剂量高达100 mg / kg导致血浆CXCL12浓度呈剂量依赖性增加。

  DOI：

  10.1021/acs.jmedchem.0c01588
• 作为产物：
  描述：

  6-氯-嘧啶-4-甲酸甲酯 在 potassium phosphate 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 lithium hydroxide monohydrate 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.75h， 生成 6-(2,4-difluorophenyl)pyrimidine-4-carboxylic acid
  参考文献：
  名称：

  发现有效的，选择性的，口服的CXCR7拮抗剂ACT-1004-1239

  摘要：

  趋化因子受体CXCR7，也称为ACKR3，是七种跨膜G蛋白偶联受体（GPCR），涉及多种病理，例如神经系统疾病，自身免疫性疾病和癌症。通过结合和清除趋化因子CXCL11和CXCL12，CXCR7调节它们的细胞外水平。在最初的高通量筛选活动中，出现了热门3。一触即发的优化导致发现了一种新型的化学型系列，例如反式外消旋化合物11i。该系列提供了可阻断CXCL11和CXCL12诱导的β-arrestin募集的CXCR7拮抗剂。11i的三取代哌啶骨架的进一步结构修饰产生具有高CXCR7拮抗活性和平衡ADMET性质的化合物。本文所述的努力最终导致了ACT-1004-1239（28f）的发现。ACT-1004-1239的生物学特性表明它是一种有效的，不可逾越的拮抗剂。在小鼠中口服ACT-1004-1239的剂量高达100 mg / kg导致血浆CXCL12浓度呈剂量依赖性增加。

  DOI：

  10.1021/acs.jmedchem.0c01588

文献信息

• [EN] KYNURENINE-3-MONOOXYGENASE INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF<br/>[FR] INHIBITEURS DE KYNURÉNINE-3-MONOOXYGÉNASE, COMPOSITIONS PHARMACEUTIQUES ET PROCÉDÉS D'UTILISATION DE CES COMPOSITIONS
  申请人：COURTNEY STEPHEN MARTIN

  公开号：WO2013033068A1

  公开（公告）日：2013-03-07

  Certain chemical entities are provided herein. Also provided are pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of KMO activity are described, which comprise administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one chemical entity as a single active agent or administering at least one chemical entity in combination with one or more other therapeutic agents. Also provided are methods for screening compounds capable of inhibiting KMO activity.

  本文提供了某些化学实体。还提供了包括至少一种化学实体和一种或多种药用可接受载体的药物组合物。描述了治疗对KMO活性抑制敏感的某些疾病和疾病的方法，包括向这些患者施用至少一种化学实体的有效量以减少疾病或疾病的体征或症状。这些疾病包括亨廷顿病等神经退行性疾病。还描述了治疗方法，包括将至少一种化学实体作为单一活性剂或将至少一种化学实体与一种或多种其他治疗剂结合使用。还提供了筛选能够抑制KMO活性的化合物的方法。
• Development of a Series of Aryl Pyrimidine Kynurenine Monooxygenase Inhibitors as Potential Therapeutic Agents for the Treatment of Huntington’s Disease
  作者：Leticia M. Toledo-Sherman、Michael E. Prime、Ladislav Mrzljak、Maria G. Beconi、Alan Beresford、Frederick A. Brookfield、Christopher J. Brown、Isabell Cardaun、Stephen M. Courtney、Ulrike Dijkman、Estelle Hamelin-Flegg、Peter D. Johnson、Valerie Kempf、Kathy Lyons、Kimberly Matthews、William L. Mitchell、Catherine O’Connell、Paula Pena、Kendall Powell、Arash Rassoulpour、Laura Reed、Wolfgang Reindl、Suganathan Selvaratnam、Weslyn Ward Friley、Derek A. Weddell、Naomi E. Went、Patricia Wheelan、Christin Winkler、Dirk Winkler、John Wityak、Christopher J. Yarnold、Dawn Yates、Ignacio Munoz-Sanjuan、Celia Dominguez

  DOI：10.1021/jm501350y

  日期：2015.2.12

  We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.
• CERTAIN KYNURENINE-3-MONOOXYGENASE INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF
  申请人：CHDI, Inc.

  公开号：EP2331095A1

  公开（公告）日：2011-06-15
• KYNURENINE-3-MONOOXYGENASE INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF
  申请人：Courtney Stephen Martin

  公开号：US20140329795A1

  公开（公告）日：2014-11-06

  Certain chemical entities are provided herein. Also provided are pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of KMO activity are described, which comprise administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one chemical entity as a single active agent or administering at least one chemical entity in combination with one or more other therapeutic agents. Also provided are methods for screening compounds capable of inhibiting KMO activity.
• US8536186B2
  申请人：——

  公开号：US8536186B2

  公开（公告）日：2013-09-17